A Series of Compounds Bearing a Dipyrido-Pyrimidine Scaffold Acting as Novel Human and Insect Pest Chitinase Inhibitors

Chitinases
not only play vital roles in the human innate immune
system but are also essential for the development of pathogenic fungi
and pests. Chitinase inhibitors are efficient tools to investigate
the elusive role of human chitinases and to control pathogens and
pests. Via hierarchical virtual screening, we have discovered a series
of chitinase inhibitors with a novel scaffold that have high inhibitory
activities and selectivities against human and insect chitinases.
The most potent human chitotriosidase inhibitor, compound 40, exhibited a Ki of 49 nM, and the most
potent inhibitor of the insect pest chitinase OfChi-h,
compound 53, exhibited a Ki of 9 nM. The binding of these two most potent inhibitors was confirmed
by X-ray crystallography. In a murine model of bleomycin-induced pulmonary
fibrosis, compound 40 was found to suppress the chitotriosidase
activity by 60%, leading to a significant increase in inflammatory
cells and suggesting that chitotriosidase played a protective role.